Morimoto, Junko Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Matsumoto, Minoru Tokushima University Tokushima University Educator and Researcher Directory
Miyazawa, Ryuichiro Tokushima University Tokushima University Educator and Researcher Directory
Yoshida, Hideyuki RIKEN
Tsuneyama, Koichi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Impaired production of thymic regulatory T cells (Tregs) is implicated in the development of Aire-dependent autoimmunity. Because Tregs require agonistic T cell receptor stimuli by self-antigens to develop, reduced expression of self-antigens from medullary thymic epithelial cells (mTECs) has been considered to play a major role in the reduced Treg production in Aire deficiency. Here, we show that mTECs abnormally express co-inhibitory receptor CTLA-4 if Aire is non-functional. Upon binding with CD80/CD86 ligands expressed on thymic dendritic cells (DCs), the ectopically expressed CTLA-4 from Aire-deficient mTECs removes the CD80/CD86 ligands from the DCs. This attenuates the ability of DCs to provide co-stimulatory signals and to present self-antigens transferred from mTECs, both of which are required for Treg production. Accordingly, impaired production of Tregs and organ-specific autoimmunity in Aire-deficient mice are rescued by the depletion of CTLA-4 expression from mTECs. Our studies illuminate the significance of mTEC-DC interaction coordinated by Aire for the establishment of thymic tolerance.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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celrep_38_7_110384.pdf 4.24 MB
Institute of Advanced Medical Sciences